There remains a distinct need to develop new chemopreventive strategies for skin cancer, one the most commonly diagnosed forms of cancer in humans. During the previous funding cycle, we identified and characterized natural fatty acids that can act as endogenous ligands for peroxisome proliferator- activated receptor-/ (PPAR/) in skin. Moreover, we demonstrated that ligand activation of PPAR/ can effectively inhibit chemically-induced skin cancer, and that the mechanisms that underlie this chemopreventive activity include PPAR/ dependent attenuation of mitosis in premalignant oncogenic cells and modulation of inflammatory signaling. The selective nature of this inhibitory mechanism coupled with preliminary data strongly suggest that activating PPAR/ may also be effective for targeting cells with mutant p53. The former studies focused on chemically-induced skin cancer, but ultraviolet light (UV) represents the most common etiological agent causing skin cancer in humans. Thus, the present proposal builds on our former findings by examining the mechanistic role of PPAR/ in UV-induced skin cancer. The central hypothesis of this proposal is that targeting PPAR/ with a natural ligand commonly found in the diet can effectively prevent UV-induced skin cancer by modulation of the cell cycle and by epigenetically interacting with inflammatory signaling. Specific Aim 1 will determine whether PPAR/ can be targeted to prevent UV-induced skin cancer. This will include analysis that will determine whether activating PPAR/ with synthetic or natural ligands can prevent and/or inhibit UV-induced skin cancer. Specific Aim 2 will determine whether activating PPAR/ can preferentially target p53 mutant cells to prevent UV-induced skin cancer. This will include analysis that will determine whether PPAR/ can prevent and/or regress mutant p53 formation in keratinocytes, whether targeting PPAR/ in basal keratinocyte inhibits p53 mutant patches, and whether PPAR/ interactions with p107/p130 mediated preferential targeting of cells with mutant p53. Specific Aim 3 will determine if attenuation of pro-inflammatory signaling by PPAR/ in keratinocytes inhibits UV-induced skin cancer. This will include analysis that will determine whether a non-PPRE driven PPAR/ mechanism (epigenetic) inhibits UVB- induced pro-inflammatory signaling in keratinocytes, and whether a non-PPRE driven PPAR/ mechanism inhibits UVB-induced skin cancer. This analysis will take advantage of unique transgenic models and cell based models to test these hypotheses. Results from these novel and innovative studies will provide the framework for future clinical trials that will target PPAR/ in conjunction with other molecular targets for skin cancer chemoprevention. Moreover, results could provide framework for screening of effective compounds that can activate either PPRE-driven and/or epigenetic pathways for selective modulation of PPAR/ for chemoprevention.